Method for producing biologically ingestible microparticles, biologically ingestible microparticles, and dispersion and pharmaceutical composition containing the same

Abstract

A method of separating biologically ingestible microparticles is used to obtain biologically ingestible microparticles in a thin film fluid formed between two processing surfaces provided with a solution containing a first solvent in which an objective substance to be pulverized is dissolved and a solvent capable of serving as a second solvent in which the solubility of the microparticles is lower than in the first solvent, the two processing surfaces being arranged so as to be able to approach to and separate from each other, at least one of which rotates relative to the other.

In the method for producing biologically ingestible microparticles by separating raw materials of biologically ingestible microparticles by a neutralization reaction in a fluid, the fluid is formed into a thin film fluid between two processing surfaces arranged so as to be able to approach to and separate from each other, at least one of which rotates relative to the other, and biologically ingestible microparticles are separated by a neutralization reaction in the thin film fluid.

A solution containing a first solvent in which a chemical as a main eye drop component is dissolved, and a solvent capable of serving as a second solvent in which the solubility of the chemical is lower than in the first solvent, are mixed in a thin film fluid formed between two processing surfaces arranged so as to be able to approach to and separate from each other, at least one of which rotates relative to the other, thereby separating drug particles and providing suspended eye drops based on the drug particles.

Description

TECHNICAL FIELD[0001]The present invention relates to a method for producing biologically ingestible microparticles, wherein the microparticles excellent in redispersibility can be formed easily and uniformly in a large amount with high energy efficiency. The present invention also relates to biologically ingestible microparticles produced by the production method, as well as a dispersion and a pharmaceutical composition containing the same.BACKGROUND ARTPatent Document 1: JP-A H04-295420Patent Document 2: JP-A 2006-104193Patent Document 3: JP-A H07-277729Patent Document 4: JP-A 2005-270745Patent Document 5: JP-A 2003-159696Patent Document 6: JP-A 2003-210957Patent Document 7: JP-A H06-227967Patent Document 8: JP-A 2007-77061[0002]Non-Patent Document 1: “Nanotechnology Handbook, Part I, Creation”, first edition, first print, 2003, published by Ohmsha Ltd. (Kandanishiki-cho 3-1, Chiyoda-ku, Tokyo, JP)[0003]The nanotechnology attracts a great deal of attention as a scientific technolo...

AI Technical Summary

Benefits of technology

[0047]The present invention makes it possible that various kinds of biologically ingestible microparticles not accompanied by unacceptable contamination can be prepared. Further, single crystals can be stably obtained, and thus mass production is feasible with high production efficiency. Moreover, a method in which drug particle diameters can be freely controlled by regulating the distance between processing surfaces arranged to be opposite to each other, without causing unacceptable dust levels occurred in the conventional dry crushing method or without abrasion of media by wet crushing, is provided. In addition, more inexpensive drugs can be provided by reducing the processing time which may otherwise cause the problem of growth of bacteria.

[0048]The present invention also makes it possible that a pharmaceutical composition exhibiting unexpectedly high biological availability, and a pharmaceutical composition containing a low water-soluble drug and being suitable for intravenous injection, can be provided.

[0049]The biologically ingestible microparticles obtained in the present invention are superior in redispersibility to those obtained by the conventional methods and can provide monodisperse biologically ingestible microparticles not causing aggregation. Depending on a necessary amount of production, an apparatus effecting the present invention can be developed in size by using general scale-up concept. Further, the present invention can improve energy efficiency as compared with the conventional methods.

[0050]In the production method of the present invention, aseptic filtration is also possible. The dispersant when used as suspended dye drops is excellent in corneal permeability. As compared with the case where raw materials of biologically ingestible microparticles are sterilized by dry heat and mechanically crushed or dispersed, the time for reaching the same final particle diameter can be significantly reduced.

Problems solved by technology

On the other hand, a long time for development and depletion of possible substances become problematic in creation of a new possible substance for drugs and medicines, and one of such causes is that the possible compound is poorly water-soluble so that a change in the structure of the compound may be necessary and thus the development may be increasingly delayed or deadlocked.

Because possible compounds selected to be developed are low in solubility, there is also a problem that not only formulation of drugs and medicines but a toxicity test and evaluation of their dynamics cannot be advanced.

However, some compounds are highly membrane-permeable even being low in solubility in water, and can be sufficiently absorbed after oral administration, so that when compounds are dropped in view of solubility only, promising compounds may be also left out.

It is reported that, in many cases, even a poorly water-soluble drug, when finely pulverized, increases its surface area and increases the rate of dissolution, thereby increasing absorption into the living body.

In the case of the mechanical crushing style, however, there is a fundamental limit to the degree of pulverization by crushing, and there are problems of, for example, mix of impurities and lack of purity in products, since use of a crushing force generated by contacting a medium mill inevitably causes mix of broken particles of bead itself.

Further, enormous energy is required, so that at present there is also a problem in energy costs.

The laser ablation method is a process of utilizing a crushing force by strong light, and thus the possibility of photodecomposition at the molecular level cannot be denied.

Accordingly, the utility value of the product may be deteriorated, or anomalies such as increase of viscosity in the dispersion system as a whole may be caused, so that there are many problems in the crushing methods themselves.

As for mix of foreign materials due to, for example, abrasion of media, it is merely referred to therein as not causing unacceptable contamination, and a risk of mix of foreign materials may arise a critical problem for pharmaceutical preparations in which high qualities always are required.

In a batch system, controlling temperature in the batch is generally difficult, and so is conducting a uniform reaction.

Further, the control of concentration in a completely uniform state is not feasible, and thus the control of reaction conditions is difficult.

Further, the yield is low, so a gaseous phase method cannot be said to be very suitable for mass production in view of production costs.

Furthermore, it is a problem that the nanoparticles obtained by a gaseous phase method are readily aggregated and fused together while a size of the particles varies, since the particles are microparticles of a pure substance.

However, when the microparticles are produced by these methods, the methods are not applicable to all the reactions, since the micro-flow path is closed with high possibility by clogging of the flow path with bubbles and byproducts generated by the reaction, and the reactions are allowed to proceed fundamentally by molecular diffusion only.

The microchemical process uses a scale-up method of increasing the number of reactors arranged in parallel, but a problem is that because the manufacturing ability of one reactor is small, and scaling up in a large volume is not practical, and the respective reactors are difficult to be supplied with the same performance, thus failing to provide uniform products.

When the reaction solution is highly viscous or the reaction causes increasing viscosity, very high pressure is necessary for passing of the solution through a minute flow path, so it concerns that a usable pump is limited, and leakage of the solution from an apparatus cannot cease due to the high pressure.

Also, when pulverization is done with a crushing device using media, mix of a media-derived foreign material is inevitable.

Further in the process for producing biologically ingestible microparticles, mix of a foreign material and growth of bacteria in the process may cause a problem too, so the proposal of a production method capable of providing biologically ingestible microparticles in a safer and more inexpensive way by reducing production time is required.

Some poorly water-soluble drugs are soluble not only in organic solvents but also in acidic or alkaline solutions, but many of the drugs are known to be poor in stability of compounds in aqueous solutions in which they have been dissolved.

However, the diameter of drug particles in aqueous suspended eye drops commercially available is several μm to several dozen μm, and thus these aqueous suspended eye drops are hardly subjected to filtering sterilization.

During sterilization, a surface modifier / particle-solving agent is separated, which is accompanied by coarsened particles, and thus it is difficult to maintain dispersibility (JP-A H06-227967 / Patent Document 7).

When the dry heat sterilization of the main raw material is conducted, the thermal denaturation, adhesion and strong aggregation of the main raw material are caused, and thus mechanical crushing and dispersion treatment for a longer time are necessary, and as a result, an aseptic operation for a long time is required.

In the case of the production method involving such aseptic operations, it costs for the aseptic facilities and operations, and aspects of production such as workability and of quality assurance such as maintenance of asepsis matter.

However, the conventional mechanical production method requires a long time in pulverization and suffers from problems such as productivity and increasing burden of costs due to high processing energy and complexity of the process.

Further, many of pulverizing machines use media, which indicates mix of media as foreign material and difficulty in acquisition of uniform particles and easy aggregation.

The methods other than the microparticulation method depend on physical properties of individual drugs and are thus not always applicable to every drug.

The microparticulation method of crushing by a mechanical means can be applied widely to drugs, but there are problems such as easy aggregation, difficulty in acquisition of uniform particles, and mix of impurities in the crushing process.

Generally, a pharmaceutical preparation is heat-labile, so that in the dry crushing method, there are problems due to heat generation during crushing process such as conversion into an amorphous compound, and occurrence of dust.

The wet crushing method also suffers from problems such as a long processing time, and difficulty in regulating the diameter of attained particles.

Further, use of media inevitably causes mix of a foreign material attributable to abrasion of the media, and the mixed foreign material is difficult to be isolated, thus making the resulting particles unusable in products requiring high purity.

In most cases, it takes long time for the wet crushing as described above to process, so that bacteria may grow over the time.

In addition, a great burden of costs out of high processing energy and complexity of the process is concerned.

If it takes a long time to mix a solution of such a compound with a new solvent, separation of crystals is initiated in its solution in a state of nonuniform concentration, then particles having broad particle size distribution / particle diameter distribution, and coarse particles, depending on growth of crystals, are mixed, resulting in not obtaining the objective crystals having sharp particle size distribution / particle diameter distribution.

Images